Radioactive compositions and complexes have found increasing diagnostic and therapeutic applications. For diagnostic purposes, radioactive complexes have been used to provide both negative and positive images of body organs, skeletal images and the like. 99m-Tc-diphosphonate radiopharmaceuticals have been used for some time to image skeletal lesions, including metastatic cancer to bone. Imaging agents typically employ low energy gamma emitting isotopes which, while useful diagnostically, have little therapeutic effect.
Beta emitting isotopes have been used in the treatment of certain cancers but are not useful for diagnostic imaging. To be effective, these beta emitting radiopharmaceuticals must localize in the cancerous lesion and not be widely distributed throughout the body. For example, if a bone seeking therapeutic radiopharmaceutical fails to localize in the metastatic bone lesion, it will either provide no beneficial treatment or require such a high dose as to damage nondiseased tissues and organs.
Various pharmaceuticals have been proposed as therapeutic agents. For example, in the Journal Of Nuclear Medicine, Volume 19, number 1, page 98 (1978), it was proposed to use 32-P labelled diphosphonate to treat patients with bone metastases from prostatic carcinoma. The diphosphonates are useful since they are known to localize preferentially in bone and even more preferentially in or around the metastatic cancer tissue. Further, Mathieu et al in the International Journal of Applied Radiation and Isotopes, volume 30, pp. 725-720 (1979), showed uptake in rat models and suggested the use of a rhenium-186 labelled diphosphonate HEDP (HEDP=1-hydroxyethylidene diphosphonate) for the treatment of osseous neoplasms. A similar diphosphonate complex is disclosed in the International Journal of Applied Radiation and Isotopes, volume 33, pp. 99-103 (1982).
The rhenium complexes disclosed in these references are of little clinical value as radiopharmaceuticals because the disclosed complexes are impure mixtures of complexed rhenium, uncomplexed perrhenate, rhenium dioxide and many other as yet unidentified species. Failure to isolate the active components of these mixtures prevented appreciation that portions of these mixtures would in fact preferentially localize in or around metastatic tissue and provide radiation treatment.
Subsequent studies have demonstrated the separation of 186-Re-diphosphonate mixtures into component complexes using high performance liquid chromatography (HPLC). Further, it was shown that the HPLC isolated 186-Re-diphosphonate complexes would localize in bone lesions. See for example Nuklearmedizin 23: 81-2, (1984).
This academic study, although interesting in that it provides proof that the HPLC isolated rhenium diphosphonate complex does in fact localize in bone lesions, fails to provide a practical treatment method which can be widely used. Typical radiopharmacies simply do not have the capabilities of routinely performing complicated procedures such as high performance liquid chromatography.
These studies demonstrated that isolated rhenium complexes can localize in metastatic bone tissue but that impurities formed in the manufacture of the ligated rhenium reaction mixture prevent successful use of the unpurified reaction mixture. The known separation techniques for isolating the ligated rhenium complex are simply too complicated for routine use in a radiopharmacy.